SUMMARY The overall objective of our proposal is to understand the role of histone deacetylases (HDACs) in the regulation of neuronal survival and death. We plan to continue our research on histone deacetylase-related protein (HDRP), which we identified as a protein with strong neuroprotective activity. We found that the neuroprotective effect of HDRP is dependent on deacetylase activity which is acquired through interaction with HDAC1. More recently we discovered that HDAC3 has strong neurotoxic activity, which is also dependent on HDAC1. And like HDRP, HDAC3 interacts with HDAC1. In the first part of our proposal we will study the relationship between HDAC1, HDRP and HDAC3 in the regulation of neuronal survival. The hypothesis underlying this part of our proposal is that HDAC1 is a molecular switch that promotes both neuroprotection and neurotoxicity depending on whether it interacts with HDRP or HDAC3, respectively. A second part of our proposal focuses on HDAC3 and looks into its involvement in Huntington Disease (HD) pathogenesis. Our hypothesis is that the HDAC3 plays a pivotal role in the neurotoxic effect of mutant huntingtin (Htt) but that under normal circumstances this neurotoxicity is prevented through its sequestration by wild-type Htt. We also propose that IGF-1-Akt signaling, generally believed to protect against mutant Htt toxicity by the phosphorylating it, actually acts by inhibiting the GSK3 -mediated phosphorylation of HDAC3. The specific goals of our proposal are: Aim 1: To determine the significance of interactions between HDAC1, HDRP, and HDAC3 to the regulation of neuronal death. Aim 2: To examine the relationship between GSK3 phosphorylation and HDAC1-HDAC3 interaction. Aim 3: To identify downstream targets of HDAC3-mediated neurotoxicity. Aim 4: To study the role of HDAC3 in mutant Htt-induced neuronal death in vitro. Aim 5: To study the effect of HDAC3 deficiency on neuropathology in the R6/2 mouse model of HD. We believe our studies will shed new insight into the fundamental mechanisms regulating neuronal survival and death, as well as how these mechanisms relate to neurodegenerative brain disorders.